Original version Date: 24/07/2018

Tobramycin

1. 
   Perinatal asphyxia and therapeutic hypothermia (2,3,4).
   
2. 
   Concurrent cyclo-oxygenase inhibitors (indometacin or ibuprofen) (4,5)
   

Anaphylaxis

Trough concentrations – Targeted <2 mg/L (1,10).

Trough concentrations are not required routinely unless:

3. 
   duration of therapy is longer than 5 days –prior to dose on day 5 (10),
   
4. 
   renal impairment or perinatal hypoxia with Apgar <5 at 5 minutes and/or concomitant use of nephrotoxic agents (10) or therapeutic hypothermia (10) - prior to every dose.
   

Auditory impairment

Myasthenia gravis (maternal) and other conditions with neurotransmission depression – May cause or prolong neuromuscular blockade and respiratory paralysis

Potent diuretics: Do not give tobramycin in conjunction with ethacrynic acid, furosemide or other potent diuretics which may themselves cause ototoxicity or enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

Other neurotoxic and/or nephrotoxic agents: Avoid concurrent or sequential use of neurotoxic and/or nephrotoxic antibiotics, particularly other aminoglycosides, amphotericin B, vancomycin, ibuprofen.

Penicillins and cephalosporins: Aminoglycosides may be inactivated by solutions containing penicillin and cephalosporin antibiotics. Where feasible, give at separate sites or separate the administration time of the antibiotics. If this is not possible, flush the line well before and after giving each antibiotic. In renal impairment separate the administration of the antibiotics for the longest duration that is practical.

Ototoxicity: Auditory and vestibular impairment, hearing loss.

Endocrine: Decreased serum calcium, magnesium, potassium and sodium

Dermatologic: Dermatitis, rash, urticarial

Central nervous system: Lethargy

Haematologic: Anaemia, leucocytosis, leukocytopenia, thrombocytopenia

Gastrointestinal: Diarrhoea, vomiting

Local: Pain at injection site.

Y-site: Aciclovir, calcium chloride, calcium gluconate, ciprofloxacin, dobutamine, dopamine, fluconazole, furosemide (frusemide), adrenaline (epinephrine), linezolid, magnesium sulfate, metronidazole, morphine sulfate, noradrenaline (norepinephrine), sodium bicarbonate, vecuronium, zidovudine

All other brands: Store at room temperature below 25°C. Protect from light.

DBL: Sodium metabisulfite, disodium edetate, sulfuric acid and/or sodium hydroxide.

Pfizer: Sodium metabisulfite, disodium edetate, sulfuric acid and/or sodium hydroxide, phenol.

Tobra-Day: Sulfuric acid and sodium hydroxide.

Avent et al. (1) compared once daily dosage regimens with the more traditional multiple daily dosing regimens in 120 neonates. The new dosing regimen was 5 mg/kg once daily dosing for infants with bodyweight <1200 g who are >30 days of age and for infants with bodyweight ≥1200 g who are >7 days of age. Multiple daily regimen was 2.5 mg/kg 8-24 hourly based on the gestational and postnatal age. Drug concentrations were more likely to be within therapeutic range with increasing the dose and extending the dosing intervals.

Ototoxicity is usually irreversible. (14). Reports about ototoxicity in neonates are contradictory. Some studies report no relation, (15-17) whereas others reported a higher incidence. (18-20) Ototoxicity usually occurs in patients who have received either long or repeated courses of aminoglycosides. (21)

Tobramycin and gentamicin share similar drug behaviour in terms of volume distribution and clearance. Main differences are that tobramycin clearance and volume of distribution are higher than the respective pharmacokinetic parameters for gentamicin in neonates. (26) Avent et al. using the dose regimen recommended in this formulary found only 3% had a subtherapeutic level <5 µg/mL and only 3% exceeded upper therapeutic range of 12 μg/mL. (1) de Hoog et al. 2002 administered 4 mg/kg tobramycin to neonates within 7 days of life with dosing interval of 48 h (<32 weeks), 36 h (32-36 weeks) and 24 h (≥37 weeks). Using these dosages, the majority of infants had tobramycin peak concentrations from 5 to 10 μg/mL and trough concentrations from 0.5 to 1 μg/mL. (10)

Recommended dose regimen is based on Avent et al. 2002 in view of generalisability across all gestational and postnatal age groups. (1) (LOE III-3, GOR B)

An increased dosing interval is recommended in therapeutic hypothermia. (2,6,7,8,30) (LOE IV, GOR C)

An increased dosing interval is recommended in infants on cyclo-oxygenase inhibitors. (4,5) (LOE IV, GOR B)

Monitoring

Trough and peak concentrations are not required routinely. (1) (LOE III-3, GOR B)

Duration of therapy >5 days – Perform trough concentration prior to dose on day 5. (10) (LOE IV, GOR B)

Perinatal hypoxia – Perform trough concentrations prior to every dose. (10) (LOE IV, GOR B)

Renal impairment – Perform trough concentrations prior to every dose. (10) (LOE IV, GOR B)

Concomitant use of other nephrotoxic agents – Perform trough concentrations prior to every dose. (10) (LOE IV, GOR B)

ECMO – Perform trough concentration before 2^nd dose. (9) (LOE IV, GOR C)

Route

Intraventricular antibiotics are associated with increased mortality and should be avoided. (LOE II, GOR B)

1. 
   Avent ML, Kinney JS, Istre GR, Whitfield JM. Gentamicin and tobramycin in neonates: comparison of a new extended dosing interval regimen with a traditional multiple daily dosing regimen. American journal of perinatology. 2002;19(08):413-20.
   
2. 
   Cristea S, Smits A, Kulo A, Knibbe CA, Van Weissenbruch M, Krekels EH, Allegaert K. Amikacin pharmacokinetics to optimize dosing in neonates with perinatal asphyxia treated with hypothermia. Antimicrobial agents and chemotherapy. 2017;61(12):e01282-17.
   
3. 
   Smits A, Kulo A, van den Anker J, Allegaert K. The amikacin research program: a stepwise approach to validate dosing regimens in neonates. Expert Opin Drug Metab Toxicol 2017;13:157-66.
   
4. 
   Smits A, De Cock RF, Allegaert K, Vanhaesebrouck S, Danhof M, Knibbe CA. Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice. Antimicrob Agents Chemother 2015;59:6344-51.
   
5. 
   Allegaert K. The impact of ibuprofen or indomethacin on renal drug clearance in neonates. The Journal of Maternal-Fetal & Neonatal Medicine. 2009;22(sup3):88-91.
   
6. 
   Lutz IC, Allegaert K, de Hoon JN, Marynissen H. Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review. BMJ paediatrics open 2020;4(1).
   
7. 
   Frymoyer A, Lee S, Bonifacio SL, Meng L, Lucas SS, Guglielmo BJ, Sun Y, Verotta D. Every 36-h gentamicin dosing in neonates with hypoxic–ischemic encephalopathy receiving hypothermia. Journal of Perinatology. 2013;33(10):778-82.
   
8. 
   Bijleveld YA, De Haan TR, Van Der Lee HJ, Groenendaal F, Dijk PH, Van Heijst A, De Jonge RC, Dijkman KP, Van Straaten HL, Rijken M, Zonnenberg IA. Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia. British journal of clinical pharmacology. 2016;81(6):1067-77.
   
9. 
   Raffaeli G, Pokorna P, Allegaert K, Mosca F, Cavallaro G, Wildschut E, Tibboel D. Drug disposition and pharmacotherapy in neonatal ECMO: from fragmented data to integrated knowledge. Frontiers in pediatrics. 2019;7:360.
   
10. 
    de Hoog M, Mouton JW, Schoemaker RC, Verduin CM, van den Anker JN. Extended‐interval dosing of tobramycin in neonates: Implications for therapeutic drug monitoring. Clinical Pharmacology & Therapeutics 2002;71(5):349-58.
    
11. 
    Tobramycin. Australian Injectable Drugs Handbook 8^th edition. Accessed on 8 September 2020.
    
12. 
    MIMS online. Tobramycin. Accessed on 26 August 2020.
    
13. 
    Micromedex online. Tobramycin. Accessed on 25^th August 2020.
    
14. 
    de Hoog M, Schoemaker RC, Mouton JW, van den Anker JN. Tobramycin population pharmacokinetics in neonates. Clinical Pharmacology & Therapeutics 1997;62(4):392-9.
    
15. 
    McCracken GH Jr. Aminoglycoside toxicity in infants and children. Am J Med 1986;8O(suppl 6B):172-8.
    
16. 
    Colding H, Andersen EA, Prytz S, Wulffsberg H, Andersen GE. Auditory function after continuous infusion of gentamicin to high-risk newborns. Acta Paediatr Stand 1989;78:840-3.
    
17. 
    Adelman C, Linder N, Levi H. Auditory nerve and brain stem evoked response thresholds in infants treated with gentamicin as neonates. Ann Otol Rhinol Laryngol 1989;98(4 pt 1):283-6.
    
18. 
    Kohelet D, Usher M, Arbel E, Arlazoroff A, Goldberg M. Effect of gentamicin on the auditory brainstem evoked response in term infants: a preliminary report. Pediatr Res 1990;28:232-4.
    
19. 
    Salamy A, Eldredge L, Tooley WI-I. Neonatal status and hearing loss in high-risk infants [see omments]. J Pediatr 1989;114:847-52.
    
20. 
    Tsai CH, Tsai FJ. Auditory brainstem responses in term neonates treated with gentamicin. Acta Paediatr Sin 1992;33:417-22.
    
21. 
    McCormack JP, Jewesson PJ. A critical reevaluation of the “therapeutic range” of aminoglycosides. Clinical infectious diseases 1992;14(1):320-39.
    
22. 
    de Hoog M, van Zanten BA, Hop WC, Overbosch E, Weisglas-Kuperus N, van den Anker JN. Newborn hearing screening: tobramycin and vancomycin are not risk factors for hearing loss. The Journal of pediatrics. 2003;142(1):41-6.
    
23. 
    Wang, X., Hong, Y., Cai, P., Tang, N., Chen, Y., Yan, T., Liu, Y., Huang, Q., Li, Q., 2017. Rapid and Reliable Detection of Nonsyndromic Hearing Loss Mutations by Multicolor Melting Curve Analysis. Scientific Reports.. doi:10.1038/srep42894
    
24. 
    Dean L. Gentamicin Therapy and MT-RNR1 Genotype. In: Pratt VM, McLeod HL, Rubinstein WS, et al., eds. Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); April 29, 2015.
    
25. 
    Shah SS, Ohlsson A, Shah VS. Intraventricular antibiotics for bacterial meningitis in neonates. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD004496. DOI: 10.1002/14651858.CD004496.pub3.
    
26. 
    Valitalo PA, van den Anker JN, Allegaert K, de Cock RF, de Hoog M, Simons SH, Mouton JW, Knibbe CA. Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates. Journal of Antimicrobial Chemotherapy. 2015 Jul 1;70(7):2074-7.
    
27. 
    Sullins AK, Abdel-Rahman SM. Pharmacokinetics of antibacterial agents in the CSF of children and adolescents. Pediatric Drugs. 2013 Apr 1;15(2):93-117.
    
28. 
    Tessin I, Trollfors B, Thiringer K, et al. Concentrations of ceftazidime, tobramycin and ampicillin in the cerebrospinal fluid of newborn infants. Eur J Pediatr. 1989;148:679–81.
    
29. 
    Masvosva P, Buckingham SC, Einhaus, et al. Intraventricular and intravenous tobramycin with ceftazidime for ventriculitis secondary to pseudomonas aeruginosa. J Pediatr Pharmacol Ther. 2003;8:137–43.
    
30. 
    Choi DW, Park JH, Lee SY, An SH. Effect of hypothermia treatment on gentamicin pharmacokinetics in neonates with hypoxic-ischaemic encephalopathy: A systematic review and meta-analysis. Journal of Clinical Pharmacy and Therapeutics. 2018;43(4):484-92.